Analeptic compositions and method



United States Patent Ofitiee lifidifii'i Patented Jan. 31, 1967 3,301,759 ANALEPTIC COMPOSITIONS AND METHOD Carl D. Lunsford, Richmond, and Albert D. Cale, Jr.,

Bon Air, Va., assignors to A. H. Robins Company, Incorporated, Richmond, Va, a corporation of Virginia No Drawing. Filed May 26, 1965, Ser. No. 459,092 39 Claims. (Cl. 167-65) The present application is a continuation-in-part of our prior-filed copending application Serial No. 156,945, filed December 4, 1961, now US. Patent 3,192,221, issued June 29, 1965, in which a requirement for restriction is of record, which in turn is a continuation-impart of our previously filed application Serial No. 88,036, filed February 9, 1961, now US. Patent No. 3,192,230. The present invention relates to certain heterocyclic organic compounds which may be referred to as 4-(omega-substituted alkyl)-2-pyrrolidinones and 4-(omega-substituted alkyl)- 2-thi-onpyrrolidinones and is more particularly concerned with compositions of 4-(omega-substituted alkyl)-3,3-disu'bstituted-1-substituted-2-pyrrolidinones and 4-(omegasubstituted alkyl) 3,3 dis-ubstituted 1 substituted 2- thionpyrroli-dines and a method of treating therewith. The invention is especially concerned with such compositions and method which embody or employ a compound of the formula:

wherein: A is lower-alkyl, cycloalkyl, monocarbocyclic aryl, or monocarbocyclic aralkyl; R is loWer-alkyl, loweralkenyl, cycloalkyl, monocarbocyclic aryl, monocarbocyclic aralkyl, pyridyl, thienyl, or thenyl; R is loweralkyl, loWer-alkenyl, cycloalky 'l, cycloalkenyl, monocarboinvention will be apparent to one skilled in the art, and still other objects will become apparent hereinafter.

In the definitions of symbols in the foregoing formula and where they appear elsewhere throughout this specification, the terms have the following significance.

By monocarbocyclic aryl radical is meant an aryl radical of the benzene series, having six ring carbon atoms, and this term includes the unsubstituted phenyl radical and phenyl radicals substituted by any radical or radicals which are not reactive or otherwise interfering under conditions of the reaction, such as nitro, loweralkoxy, lower-alkyhnercapto, loWer-alkyl, halo, and the like. The substituted-phenyl radicals have preferably no more than one of three substituents such as those given above and, furthermore, these substituents can be in various available positions of the phenyl nucleus and,

. where more than one substituent is present, can be the cyclic aryl, or monocarbocyclic aralkyl; R" is hydrogen or methyl, a maximum of one R" being other than hydrogen; n .is zero or one; B is halogen, hydroxy, mercapto, lower-alkylrnercapto, loWer-alkoxy, phenoxy, benzyloxy, be-nzoyloxy, hydroxybenzoyloxy, nicotinoyloxy, loweralkanoyloxy; and E is oxygen or sulfur.

The compounds of the invention having the foregoing formula are generally characterized by important pharmacological activity, indicative of their use in counteracting certain physi-ological abnormalities in an animal body. The compounds are analeptics. Certain compounds of the series are extremely potent and long acting analeptics, stimulating respiration and antagonizing central nervous system depression and exhibiting a particularly durable antagonism against barbiturate-induced depression or poisoning at dose levels consider-ably below that at which untoward side effects appear. The omegahalo compounds are especially potent analeptics. The compounds which are strong analeptics are generally also hypertensives.

it is accordingly an object of this invention to provide novel and useful compositions embodying 4-(omega-substitutcd alkyl) -2-pyrrolidinones and -2-thionpyrrolidinones as active ingredient and a method for the treatment of a living animal ibody therewith. Other objects of the same or different and can be in various position combinations relative to each other. The lower-alkyl, loweralkoxy, and lower-alkylmercapto substituents each have preferably from one to three carbon atoms which can be arranged as straight or branched chains. A total of fifteen carbon atoms in the monocarbocyclic aryl radical is the preferred maxi-mum.

In the foregoing definition of R, certain cyclic radicals are referred to. When pyridyl is referred to, e.g., the 3- or 4-pyridyl radicals are included. When thienyl or thenyl radicals are referred to, these may be, for example, the 3-thienyl or 2- or 3-thenyl radicals.

The term loWer-alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like. The term alkenyl includes straight and branched chain radicals of two up to eight carbon atoms inclusive and includes such groups as vinyl, allyl, methallyl, 4-pentenyl, 3-hexenyl, and 3- methyl-3-heptenyl. The term cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl. The term cycloalkeny as used herein includes cyclic alkenyl radicals containing up to nine carbonatoms inclusive and encompasses such usual radicals as 1- and Z-cycl-ohexenyl and 1- and Z-cyclopentenyl. Included in the term aralkyl are loWer-alkyl substituted mono-carbocy-clic aryl groups such as benzyl, phenethyl, methyibenzyl, phenproipyl and the like. The radicals R and R in the above formula, as stated in the foregoing, are inclusive of such groups as lower-aikyl, cycloalkyl, and aralkyl, and are preferably although not necessarily radicals of a solely hydrocarbon nature.

When halogen is referred to herein, preferably but not necessarily a halogen of atomic weight in excess of 19 is employed. Of the halogens, chlorine is preferred.

The present invention provides valuable pharmaceutical compositions of pharmacological]y-active organic compounds, having an omega-substituted alkyl substituent in the four position, and a method of treating therewith. Although pyrrolidinones having substituents on the 1- nitrogen atom are known, to the best of'our knowledge no compounds of the present type, having a substituted alkyl group attached to the 4-position of the 2-pyrrclidinone or a Z-thionpyrrolidinone ring, substitution in the l-position, and disubstitution in the 3-position of said ring, have heretofore been known or preparable by any method, neither have the starting materials therefor been known heretofore. The preferred compounds for all purposes are the 3,3-diaryl compounds, especially the 1-lower-alkyl-3,3diphenyl compounds.

The compounds which are utilized as active ingredient in the compositions and method of the invention are scribed and claimed per se in parent application Serial No. 156,945, now U.S. Patent 3,192,221, and are prepared as disclosed therein. The disclosure of the said US. Patent 3,192,221 is hereby incorporated into this application in toto by reference and by reference made a part hereof. Of the compounds, falling Within the scope of the foregoing broad formula, disclosed in the said US. patent, the following type compounds and species deserve special attention:

1-lower-alkyl-3,3-diphenyl-4-(,8-haloethyl)-2-pyrrolidinones 1-lower-alkyl-3,3-dipheny1-4- (fi-chloroethyl -2-pyrrolidinones 1-isopropyl-3,3diphenyl-4- (fl-chloroethy] -2-pyrroiidinone 1-ethy1-3,3-dipl1enyl-4-(fl-chloroethyl)-2-pyrrolidinone l-lower-alky1-3 ,3-diphenyl4- gamma-halopropyl) -2- pyrrolidinones 1-lower-alkyl-3,3-diphenyl-4- fl-lower-alkoxyethyl -i.-

pyrrolidinones 1-lower-alkyl-3,3-diphenyl-4(,B-lower-alkanoyloxyethyl) Z-pyrrolidinones 1-lower-alkyl-3,3-diphenyl-4-(ti-mercaptoethyl)-2-pyrrolidinones 1-lower-alkyl-3,3-diphenyl-4- (ti-hydroxyethyl -2-pyrrolidinones 1,3-di-lower-alkyl-3-phenyl-4- ,e-haloethyl) -2-pyrrol idinones 1,3-di-loWer-alky1-3-phenyl4-(fi-chloroethyl)-2pyrrolidinones 1-lower-alky1'3-cycloalkyl-3-pheny 1-4- dhaloethyl -2- pyrrolidinones wherein the cycloalkyl group has up to and including nine carbon atoms 1-lower-alky1-3-cycloall;yl3- phenyl-4-( ,B-chloroethyl) -2- pyrrolidinones wherein the cycloalkyl group has up to and including nine carbon atoms 1-lower-all-:yl-3-phenyl-3-pyridyl-4- ,d-haloeth yl) -2-pyrrolidinones 1-lower-alkyl-3,3-diphenyl-4-(3-halo-2-propyl)-2-pyrrolidinones 1-lower-alkyl3,3-diphenyl-4-(2-halopropyl)-2-pyrrolidinones 1-1ower-alkyl-3,3-diphenyl-4-(2haloethyl)-2-pyrroiidinethiones l-lower-alkyl-3,3-diphenyl-4(Z-mercaptoethyl -2-pyrrolidinethiones Formulation and adininisti'atioli.Effective quantities of any of the foregoing pharmacologically active compounds may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions. The 1-lower-all yl-3,3-disubstituted-4-(omega-chloroalkyl)-2-pyrrolidinones and 2- thionpyrrolidinones represent a preferred group of highly active compounds, of which the 1-ethyl and l-isopropyl compounds are outstandingly active. Preferred groups at the 3-position are phenyl radicals as the 3,3-diphenyl compounds are likewise outstanding in their activity,

Although very small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above and preferably twenty-five, fifty Or one hundred milligrams or even higher, depending of course upon the emergency of the situation and the particular result desired. Five to fifty milligrams appears optimum per unit dose, while usual broader ranges appear to be one to milligrams per unit dose. The active agents of the invention may be combined with other pharmacologically active agents, or with buffers, antacids or the like, for administration and the proportion of the active agent in the compositions may be varied widely. it is only necessary that the active ingredient constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. Theexact individual dosages as well as daily dosages in a particular case will of course bedetermined according to established medical principles under the direction of a physician or veterinarian. Results upon administration of these novel materials have thus far proved extremely gratifying.

The following formulations are representative for all of the pharmacologically active compounds of the invention, but have been especially designed to embody as ac tive ingredient the 1-lower-alkyl-3,3 -diphenyl- (omegacliloroethyl)-2-pyrrolidinones and Z-thionpyrrolidinones, especially the l ethyl and l-isopropyl compounds.

FORMULATIONS (l) Capsules.Ca psules of 5 mg., 25 mg, and 50 mg. of active ingredient per capsule are prepared. With the higher amounts of active ingredient, reduction may be male in the amount of lactose.

Typical blend for encapsulation: Per capsule, mg. Active ingredient, as salt 5.0 Lactose 296.7 Starch 129.0 lViag-ncsium stearate 4.3

Total 435.0

Additional capsule formulations preferably contain a higher dosage of active ingredient and are as follows:

. I Ingredients 100 mg. per 250 mg. per 500 mg. per

Capsule Capsule Capsule tetive ingredient, as s:tlt 100. 0 250. 0 500. (1 Lactose 231. 5 126. 5 1 Starch 9t). 2 54. 2 13. 4 Magnesium Stoarate 4v 3 '1. 3 5. 5

Total, mg 435. 0 435. 0 550. 0

(1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste) 3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate -o 0.9

Total 170.1

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water. Granuiate the blend with starch paste and pass the wet mass through an eight mesh screen. The wet granulation is dried and sized through a twelve mesh screen. The dried granules are blended with the calcium stearate and compressed.

Additional tablet formulations preferably contain a higher dosage of the active ingredient and are as follows:

A. 50 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt 50.0 Lactose 90.0

Milo starch 20.0

Corn starch 38.0

Calcium stearate 2.0

Total 200.0

B. 100 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt 100.0 Lactose 190.0

Dicalcium phosphate 172.2 Starch 54.0

Milo starch 21.6

Calcium stearate 2.2

Total 540.0

C. 250 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt 250.0 Corn starch 56.0 Carbowax 6000 (polyethylene glycol of M.W.

approximately 6000) 25.0 Lactose 35.0

Magnesium stearate 4.0

Total 370.0

Uniformly blend the active ingredient, Carbowax 6000, lactose, and one-half the weight of magnesium stearate required. This blend is then slugged on a suitable tablet press. These slugs are granulated through a ten mesh screen on an oscillating granulator. These granules are then blended with the remainder of the magnesium stearate and the lubricated granules are then converted into tablets on a suitable tablet press.

D. 500 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt 500.0 Corn starch (wet) I 86.4 Milo starch -t 32.4

Calcium stearate 3.2 Corn starch (dry) 26.0

Total 648.0

Uniformly blend the active ingredient, corn starch and milo starch. This blend is wet granulated using water and the wet mass is passed through a number eight mesh screen. These wet granules are dried overnight at 140- 160 degrees Fahrenheit. The dried granules are passed through a number ten mesh screen. The dried granules and weighed amounts of corn starch and calcium stearate are uniformly blended and these lubricated granules are compressed on a suitable tablet press.

6 (3) Injectable2% sterile s0luti0n.

Per cc. Active ingredient mg 20 Preservative, e.g., chlorobutanol percent wt./vol 0.5 Water for injection, q.s.

Prepare solution, clarify by filtration, fill into vials,

seal, and autoclave.

(4) The pharmacologically active compounds provided by the present invention may also be administered successfully by embodying an effective quantity thereof in an injectable suspension for injection into an animal body, in oral powders, suspensions or syrups, and in other acceptable dosage forms.

Representative compositions of the present invention were tested against a known analeptic, nikethamide. As purchased on the open market, this compound was sunplied as a 250 mg./ml. aqueous solution.

OBJECTIVE The purpose of these studies was to determine the relative activity of representative compounds in this series of compounds compared to nikethamide, a well known analeptic agent.

EXPERIMENTAL Metlz0d.-Adult mongrel dogs (either sex) were used following an overnight fast. Surgical anesthesia was induced with intravenous phenobarbital sodium, to mg./k.g. according to the requirement in each animal. The numbers of-animals employed were: 1 to 5 with each AHR compound; and 5 with nikethamide. A Grass Model 5 Polygraph was used for recording blood pressure from a carotid artery (Statham P23AC transducer) and respiration from a tracheal cannula (Grass Model PT5A Volumetric Low Pressure Transducer). Changes in the level of anesthesia were determined by gross observation of the animal and by application of stimuli appropriate for investigating the functional integrity of pain, blink and corneal reflexes.

Aqueous or propylene glycol solutions of experimental compounds were administered via a femoral vein. In most instances the initial dose was 1 mg./kg. and each subsequent dose was doubled at 10 to 30 minute intervals until pharmacologic and/ or lethal effects were produced. If such doses proved to be too high (e.g., certain AHR compounds) or too low (e.g., nikethamide), the proper adjustment was made in subsequent experiments.

Results.- The results of this study are summarized in Table I. All AHR compounds were capable of markedly increasing the depth and frequency of breathing (respiration). In addition to the respiratory effect, all AHR compounds were found to be potent antagonists of the central nervous system depressant properties of the anesthetic agent.

Both magnitude and duration of the stimulant effect on respiration of the anesthetized dog were increased as the dose of AHR compounds was increased. Indeed, it was frequently possible to stimulate respiration for several hours following a single injection. Analeptic effects, such as restoration of the integrity of blink, corneal, and pain reflexes, increased skeletal muscular tone, and spontaneous body movements occurred consistently with the 1,3,3,4-tetra-substituted-2-pyrrolidinones.

In contrast to the 1,3,3,4-tetra-substituted-Z-pyrrolidinones and thionpyrrolidinones, nikethamide was found to exert a weak and transient stimulant effect on respiration. Intravenous doses of 40 to 80 mg./kg. were necessary to produce a modest etfect on respiration. The respiratory effect of nikethamide was extremely brief in nature no matter what dose was used. Doses as high as 640 mg./kg. failed to elicit any observable analeptic effects such as a restoration of blink, corneal, or pain reflexes. Spontaneous body movements were never observed following treatment with nikethamide.

TABLE {Comparative activity of 13,3A-tctrn-snbstituted-2- n'rrolidinonos and thionpyrrolidinoncs with nikethnniide] min m-on o n x Minimum Ei'l'ectivo IV l )osu (mg/kg.) with regard to Ai'lR A R X Respiratory A nalcptic Stimulation E Heetsi 547 Pheuyl Methyl d Ethyl. 1 to n a lsopropyl 1 5 lsoluityl 4 4 Cyclohcxylu 1 1 B onizyl 1t] 4 8 to 16 2 to 4 4 to 16 8 1G lie. 1 2 to e EthyL l 4 M. .(i 2 2 lsopropyL 1 1 l ienyl .do 2 4 to S Nikcthaini t .1 40-80 040 return oi blink and/or corneal reflexes,

increased skeletal muscular tone, body movements, ability to respond to auditory and/or visual stimuli.

Summury.The foregoing table shows clearly that the beta-halocthyl compounds and beta-acyloxyethyl compounds are far superior to nikethamide.

The activity of the active agentsof the present invention, as evidenced by tests in lower animals, is indicative of utility based on their valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions.

Various modifications and equivalents will be apparent to one skilled in the art and may be made in the compounds, compositions, and methods of the present invention without departing from the spirit or cope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.

We claim:

1. A process which comprises administering to a living animal body, for its analeptic effect, an effective amount of a compound selected from the group consisting of 4- (omega-substituted alkyl)-2-pyrrolidinones and -2-thionpyrrolidinones of the formula:

wherein B is selected from the group consisting of halogen, hy-

droxy, mercapto, lower-alkylmercapto, lower-alkoxy, phenoxy, benzyloxy, benzoyloxy, hydroxybenzoyloxy, nicotinoyloxy, and lower-alkanoyloxy,

A is selected from the group consisting of lower-alkyl, cycloalkyl having up to a maximum of nine carbon atoms, monocarbocyclic aryl, and monocarbocyclic aralkyl,

R is selected from the group consisting of lower-alkyl, lower-alkenyl, cycloalltyl having up to a maximum of nine carbon atoms, monocarbocyclic aryl, .monocarbocyclic aralkyl, yridyl, thienyl, and thenyl,

R is selected from the group consisting of lower-alkyl, lower-alkenyl, cycloalkyl having up to a maximum of nine carbon atoms, cycloalkenyl having up to a maximum of nine carbon atoms, and monocarbocyclic aralkyl,

R is selected from the group consisting of hydrogen and methyl, a maximum of one 1 being other than hy drogen,

wherein E is selected from the group consisting of oxygen and sulfur,

wherein monocarbocyelic aryl and monocarbocyclic aralkyl has at most fifteen carbon atoms and has a radical which is selected from the group consisting of phenyl, nitrophenyl, lower-alkoxyphenyl, lowerall;ylmercaptophenyl, lower-alliylphenyl, and halophenyl, and wherein alkyl in aralkyl is lower-alkyl, and wherein 11 is selected from Zero and one.

2. A process according to claim 1, wherein the active ingredient is administered together with a pharmaceutically acceptable carrier therefor and in an amount of about one to 100 milligrams.

n is selected from zero and one.

3. The process of claim 2 wherein the active compound is 1 lower-alkyl-3,3-diphenyl-4-(p-haloethyl)-2-pyrrolidinone.

4. The process of claim 2 wherein the active compound is 1 lower-alkyl-3,3-diphenyl-4-(fi-chloroethyl)-2-pyrrolidinone.

5. The process of claim 2 wherein the active compound is 1 isopropyl-3,3-diphenyl-4-(dchloroethyl)-2-pyrrolidinone.

6. The process of claim 2 wherein the active compound is 1-ethyl-3,3-diphenyl-4(B-chloroethyl)-2-pyrrolidinone.

7. The process of claim 2 wherein the active compound is 1-lower-alkyl-3,3-diphenyl-4-(gamma-halopropyl)-2-pyrrolidinone.

8. The process of claim 2 wherein the active compound is l-lower-alkyl-3,3diphenyl-4-(fi-lower-alkoxyethyl )-2-pyrrolidinone.

9. The process of claim 2 wherein the active compound is 1 lower-alkyl-3,3-diphenyl-4-(,B-lower-alkanoyloxyethyl)-2-pyrrolidinone.

10. The process of claim 2 wherein the active compound is 1-lower-alkyl-3,3-diphenyl-4-(fl-mercaptoethyl)- 2-pyrr0lidinone.

11. The process of claim 2 wherein the active compound is 1-lower-alkyl-3,3-diphenyl-4-(fl-hydroxyethyl)- 2-pyrrolidinone.

12. The process of claim 2 wherein the active compound is 1,3 di-lower-alkyl-3-phenyl-4-(,B-haloethyl)-2- pyrrolidinone.

13. The process of claim 2 wherein the active compound is l,3-di-lower-alkyl-3-phenyl-4-(fl-chloroethyl)-2- pyrrolidinone.

14. The process of claim 2 wherein the active compound is 1 lower-alkyl-3-cycloalkyl-3-pheny1-4-(fl-haloethyl)-2-pyrrolidinone wherein the cycloalkyl group has up to and including nine carbon atoms 15. The process of claim 2 wherein the active compound is 1 lower-alkyl-3-cycloalkyl-3-phenyl-4-(/i-chloroethyl)-2-pyrrolidinone wherein the cycloalkyl group has up to and including nine carbon atoms.

16. The process of claim 2 wherein the active compound is 1-lower-alkyl-3-phenyl-3-pyridyl-4a(/3-haloethy-l)- Z-pyrrolidinone.

17. The process of claim 2 wherein the active compound is 1-lower-al-kyl-3,3-diphenyl-4-(3-halo-2-propyl)- 2-pyrrolidinone.

18. The process of claim 2 wherein the active compound is 1-lower-alkyl-3,3-diphenyl-4-4(2-halopropyl)-2- pyrrolidinone.

19. The process of claim 2 wherein the active compound is 1-lower-alkyl-3,3-diphenyl-4- (2-haloethyl)-2- pyrrolidinethion.

20. The process of claim 2 wherein the active compound is 1-lower-alky1-3,3-dipheny1-4-(Z-mercaptoethyl)- Z-pyrrolidinethion.

21. A pharmaceutical composition, useful for its analeptic effect, comprising (a) an effective amount of about one to 100 milligrams of a compound of the formula:

R is selected from the group consisting of lower-alkyl,

alkyl has at most fifteen carbon atoms and has a radical which is selected from the group consisting of phenyl,

nitrophenyl, lower-alkoxyphenyl, lower-alkylmercaptophenyl, lower-alkylphenyl, and halophenyl, and wherein alkyl in aralkyl is lower-alkyl, and wherein n is selected from'zero and one,

and (b) a pharmaceutically acceptable carrier therefor.

22. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(fl-haloethyl) -2-pyr-rolidinone.

23. A composition according to claim 21, wherein the active ingredient is 1-lower-alky1-3,3-diphenyl-4-(B-chloroethyl) -2-pyrrolidinone.

24. A composition according to claim 21, wherein the active ingredient is 1-isopropyl-3,3-diphenyl-4-(5-chloroethyl) -2-pyrrolidinone.

25. A composition according to claim 21, wherein the active ingredient is 1-ethyl-3,3-diphenyl-4-(fl-chloroethyl)- 2-pyrrolidinone.

26. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(gammahalopropyl) -2-pyrrolidinone.

27. A composition according to claim 21, wherein the active ingredient is 1-lower-alky-l-3,3-diphenyl-4-( 3-loweralkoxyethyl) -'2-pyrrolidinone.

28. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(}8-loweralkanoyloxyethyl) -2-pyrrolidinone.

29. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(fi-mercapt oethyl) -2-pyr-rolidinone.

30. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-( ii-hydroxyethyl) -2-pyrrolidinone.

31. A composition according to claim 21, wherein the active ingredient is l,3-di-lower-alkyl-3-phenyl-4-(B-haloethyl) -2-py-rrolidinone.

32. A composition according to claim 21, wherein the active ingredient is 1,3 di-lower-alkyl-3-phenyl-4-(13- chloroet'hyl) -2-pyrrolidinone.

33. A composition according to claim 21, wherein the active ingredient is 1-lower alkyl-3-cycloalkyl-3-phenyl-4- (fi-haloethyl)-2-pyrrolidinone wherein the cycloalkyl group has up to and including nine carbon atoms.

34. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3-cycloalkyl-3-phenyl-4- (ti-chloroethyl)-2-pyrrolidinone wherein the cycloalkyl group has up to and including nine carbon atoms.

35. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3-phenyl-3-pyridyl-4- fi-h aloethyl -2-pyrrolidinone.

36. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(3- halo- 2-propyl) -2-pyrrolidinone.

37. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(2-halopro pyl) 2-py1-rolidinone.

38. A composition according to claim 21, wherein the active ingredient is 1-lower-alkyl-3,3-diphenyl-4-(2-haloethyl) -2-pyrrolidinethion.

39. A composition according to claim 21, wherein the active ingredient is 1-lower-a1kyl-3,3-diphenyl-4-(2-mercaptoethyl)-2-pyrrolidinethion.

No references cited.

JULIAN S. LEVITT, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner. 

1. A PROCESS WHICH COMPRISES ADMINISTERING TO A LIVING ANIMAL BODY, FOR ITS ANALPTIC EFFECT, AN EFFECTIVE AMOUNT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4(OMEGA-SUBSTITUTED ALKYL)-2-PYRROLIDINONES AND -2-THIONPYRROLIDINONES OF THE FORMULA: 